Pneumologie 2017; 71(03): 151-163
DOI: 10.1055/s-0042-123803
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

„Liquid biopsy“: Analyse molekularer Marker aus Blutproben zur Therapiesteuerung beim Lungenkarzinom

Liquid Biopsy: Detection of Molecular Markers for Treatment Decisions in Lung Cancer
W. M. Brückl
1   Universitätsklinik für Pneumologie, Allergologie und Schlafmedizin, Paracelsus Medizinische Privatuniversität, Nürnberg
2   Medizinische Klinik 3 (Pneumologie, Allergologie, Schlafmedizin), Klinikum Nürnberg, Nürnberg
,
R. M. Wirtz
3   Institut für Pathologie, St. Elisabeth Krankenhaus, Köln
4   STRATIFYER Molecular Pathology GmbH, Köln
,
T. Bertsch
5   Universitätsinstitut für Klinische Chemie, Laboratoriumsmedizin und Transfusionsmedizin – Zentrallaboratorium, Paracelsus Medizinische Privatuniversität, Nürnberg
6   Institut für Klinische Chemie, Laboratoriumsmedizin und Transfusionsmedizin – Zentrallaboratorium, Klinikum Nürnberg, Nürnberg
,
J. H. Ficker
1   Universitätsklinik für Pneumologie, Allergologie und Schlafmedizin, Paracelsus Medizinische Privatuniversität, Nürnberg
2   Medizinische Klinik 3 (Pneumologie, Allergologie, Schlafmedizin), Klinikum Nürnberg, Nürnberg
,
A. Jung
7   Pathologisches Institut der Ludwig-Maximilians Universität München
› Author Affiliations
Further Information

Publication History

eingereicht01 September 2016

akzeptiert nach Revision09 December 2016

Publication Date:
14 February 2017 (online)

Zusammenfassung

Zielgerichtete Therapien haben erfolgreich Einzug in die palliative Therapie des Lungenkarzinoms gehalten, da sie eine Individualisierung oder Personalisierung ermöglichen, die mit der Testung von prädiktiven Biomarkern einhergeht. Dadurch steigt die Zahl an prädiktiven molekularbiologischen und immunhistochemischen Untersuchungsmöglichkeiten zu verschiedenen Zeitpunkten der Therapie und damit der Bedarf an jeweils aktuellen Tumorgewebeproben. Diese sind jedoch oft nicht ohne unverhältnismäßig hohe Belastungen für den Patienten zu gewinnen. Daher stellen Verfahren der Diagnostik aus Blutproben, die mit dem aus dem Englischen stammenden Begriff „liquid biopsy“ zusammengefasst werden, eine Alternative bzw. Ergänzung zur klassischen Gewebebiopsie dar. Derzeit können in der klinischen Routine bereits aktivierende EGFR-Mutationen sowie die inhibitorische Mutation T790 M aus dem Blut detektiert werden. Dieser Artikel stellt den aktuellen Stellenwert der liquid biopsy in der Diagnostik, zur Prognose und zur Steuerung des Therapieverlaufs bei Lungenkarzinomen dar und gibt einen Ausblick auf zukünftige Möglichkeiten.

Abstract

Personalized, individualized, targeted therapy has successfully found entrance in the palliative treatment of lung cancer as they enable a personalized and individualized strategy going ahead with biomarker testing. Due to the crescending amount of predictive molecular and immunhistochemical analyses at different time points during therapy the need for more and actual tumor tissue increases; however these samples cannot always be obtained without major discomfort for the patients. Therefore, analyses from blood, the so called „liquid biopsy“, is an alternative or additional method. Activating mutations in the EGFR gene and the inhibitory mutation T790 M can already be detected from blood during clinical routine. This review presents the status of liquid biopsy for diagnosis, prognosis and as predictive parameter during the course of therapy in lung cancer and gives an outlook on future developments.

 
  • Literatur

  • 1 Herbst RS, Heymach JV. Lippman SM. Lung cancer. N Engl J Med 2008; 359: 1367-1380
  • 2 Weinstein IB. Cancer. Addiction to oncogenes – the Achilles heel of cancer. Science 2002; 297: 63-64
  • 3 De Luca A, Normanno N. Predictive biomarkers to tyrosine kinase inhibitors for the epidermal growth factor receptor in non-small-cell lung cancer. Curr Drug Targets 2010; 11: 851-864
  • 4 Thatcher N, Hirsch FR, Luft AV. et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763-774
  • 5 Slavova-Azmanova NS, Lizama C, Johnson CE. et al. Impact of the introduction of EBUS on time to management decision, complications, and invasive modalities used to diagnose and stage lung cancer: a pragmatic pre-post study. BMC Cancer 2016; 16: 44
  • 6 Rooper LM, Nikolskaia O, Carter J. et al. A single EBUS-TBNA procedure can support a large panel of immunohistochemical stains, specific diagnostic subtyping, and multiple gene analyses in the majority of non-small cell lung cancer cases. Hum Pathol 2016; 51: 139-145
  • 7 Fenizia F, De Luca A, Pasquale R. et al. EGFR mutations in lung cancer: from tissue testing to liquid biopsy. Future Oncol 2015; 11: 1611-1623
  • 8 Hamilton G, Rath B, Klameth L. et al. Receptor tyrosine kinase expression of circulating tumor cells in small cell lung cancer. Oncoscience 2015; 2: 629-634
  • 9 Hamilton G, Rath B, Ulsperger E. How to target small cell lung cancer. Oncoscience 2015; 2: 684-692
  • 10 Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem 2015; 61: 112-123
  • 11 Sparano A, Chernock R, Feldman M. et al. Extending the inferior limits of supracricoid partial laryngectomy: a clinicopathological correlation. Laryngoscope 2005; 115: 297-300
  • 12 Cai W, Lin D, Wu C. et al. Intratumoral Heterogeneity of ALK-Rearranged and ALK/EGFR Coaltered Lung Adenocarcinoma. J Clin Oncol 2015; 33: 3701-3709
  • 13 Jiang T, Ren S, Zhou C. Role of circulating-tumor DNA analysis in non-small cell lung cancer. Lung Cancer 2015; 90: 128-134
  • 14 Stroun M, Maurice P, Vasioukhin V. et al. The origin and mechanism of circulating DNA. Ann N Y Acad Sci 2000; 906: 161-168
  • 15 Jahr S, Hentze H, Englisch S. et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001; 61: 1659-1665
  • 16 Diehl F, Li M, Dressman D. et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A 2005; 102: 16368-16373
  • 17 Fan HC, Blumenfeld YJ, Chitkara U. et al. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci U S A 2008; 105: 16266-16271
  • 18 Bettegowda C, Sausen M, Leary RJ. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6: 224ra24
  • 19 Diaz Jr LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014; 32: 579-586
  • 20 Esposito A, Bardelli A, Criscitiello C. et al. Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat Rev 2014; 40: 648-655
  • 21 Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011; 11: 426-437
  • 22 Jung M, Klotzek S, Lewandowski M. et al. Changes in concentration of DNA in serum and plasma during storage of blood samples. Clin Chem 2003; 49: 1028-1029
  • 23 Medina Diaz I, Nocon A, Mehnert DH. et al. Performance of Streck cfDNA Blood Collection Tubes for Liquid Biopsy Testing. PLoS One 2016; 11: e0166354
  • 24 Gaspare L, Machiwa JF, Mdachi SJ. et al. Polycyclic aromatic hydrocarbon (PAH) contamination of surface sediments and oysters from the inter-tidal areas of Dar es Salaam, Tanzania. Environ Pollut 2009; 157: 24-34
  • 25 Thijssen MA, Swinkels DW, Ruers TJ. et al. Difference between free circulating plasma and serum DNA in patients with colorectal liver metastases. Anticancer Res 2002; 22: 421-425
  • 26 Norton SE, Luna KK, Lechner JM. et al. A new blood collection device minimizes cellular DNA release during sample storage and shipping when compared to a standard device. J Clin Lab Anal 2013; 27: 305-311
  • 27 Ma M, Zhu H, Zhang C. et al. “Liquid biopsy”-ctDNA detection with great potential and challenges. Ann Transl Med 2015; 3: 235
  • 28 Thress KS, Brant R, Carr TH. et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer 2015; 90: 509-515
  • 29 Ignatiadis M, Lee M, Jeffrey SS. Circulating Tumor Cells and Circulating Tumor DNA: Challenges and Opportunities on the Path to Clinical Utility. Clinical Cancer Research 2015; 21: 4786-4800
  • 30 Powell AA, Talasaz AH, Zhang H. et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One 2012; 7: e33788
  • 31 Krebs MG, Metcalf RL, Carter L. et al. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat Rev Clin Oncol 2014; 11: 129-144
  • 32 Dahl E, Jung A, Fassunke J. et al. [Chances and risks of blood-based molecular pathological analysis of circulating tumor cells (CTC) and cell-free DNA (cfDNA) in personalized cancer therapy: positional paper from the study group on liquid biopsy of the working group for molecular pathology in the German Society of Pathology (DGP)]. Pathologe 2015; 36: 92-97
  • 33 Alix-Panabieres C, Pantel K. Technologies for detection of circulating tumor cells: facts and vision. Lab Chip 2014; 14: 57-62
  • 34 Harouaka R, Kang Z, Zheng SY. et al. Circulating tumor cells: advances in isolation and analysis, and challenges for clinical applications. Pharmacol Ther 2014; 141: 209-221
  • 35 Parkinson DR, Dracopoli N, Petty BG. et al. Considerations in the development of circulating tumor cell technology for clinical use. J Transl Med 2012; 10: 138
  • 36 Cohen SJ, Punt CJ, Iannotti N. et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 3213-3221
  • 37 Cristofanilli M, Budd GT, Ellis MJ. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781-791
  • 38 de Bono JS, Scher HI, Montgomery RB. et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008; 14: 6302-6309
  • 39 Cayrefourcq L, Mazard T, Joosse S. et al. Establishment and characterization of a cell line from human circulating colon cancer cells. Cancer Res 2015; 75: 892-901
  • 40 Hodgkinson CL, Morrow CJ, Li Y. et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med 2014; 20: 897-903
  • 41 Yu M, Bardia A, Aceto N. et al. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 2014; 345: 216-220
  • 42 Zhang L, Ridgway LD, Wetzel MD. et al. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med 2013; 5: 180ra148
  • 43 Gasch C, Bauernhofer T, Pichler M. et al. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin Chem 2013; 59: 252-260
  • 44 Muller C, Holtschmidt J, Auer M. et al. Hematogenous dissemination of glioblastoma multiforme. Sci Transl Med 2014; 6: 247ra101
  • 45 Wang J, Wang K, Xu J. et al. Prognostic significance of circulating tumor cells in non-small-cell lung cancer patients: a meta-analysis. PLoS One 2013; 8: e78070
  • 46 George JN. Platelets. Lancet 2000; 355: 1531-1539
  • 47 Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science 2010; 328: 562-564
  • 48 Best Myron G, Sol N, Kooi I. et al. RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. Cancer Cell 2015; 28: 666-676
  • 49 Klement GL, Yip TT, Cassiola F. et al. Platelets actively sequester angiogenesis regulators. Blood 2009; 113: 2835-2842
  • 50 Kuznetsov HS, Marsh T, Markens BA. et al. Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells. Cancer Discov 2012; 2: 1150-1165
  • 51 McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 2014; 16: 717-727
  • 52 Nilsson RJ, Balaj L, Hulleman E. et al. Blood platelets contain tumor-derived RNA biomarkers. Blood 2011; 118: 3680-3683
  • 53 Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19: 1423-1437
  • 54 Calverley DC, Phang TL, Choudhury QG. et al. Significant downregulation of platelet gene expression in metastatic lung cancer. Clin Transl Sci 2010; 3: 227-232
  • 55 Thierry AR, Mouliere F, El Messaoudi S. et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med 2014; 20: 430-435
  • 56 Taverna S, Giallombardo M, Gil-Bazo I. et al. Exosomes isolation and characterization in serum is feasible in non-small cell lung cancer patients: critical analysis of evidence and potential role in clinical practice. Oncotarget 2016; 7: 28748-28760
  • 57 Gahr S, Stoehr R, Geissinger E. et al. EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice. Br J Cancer 2013; 109: 1821-1828
  • 58 Mok TS, Wu YL, Thongprasert S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-957
  • 59 Rosell R, Carcereny E, Gervais R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239-246
  • 60 Yang JC, Wu YL, Schuler M. et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16: 141-151
  • 61 Lynch TJ, Bell DW, Sordella R. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129-2139
  • 62 Bruckl WM, Wiest GH, Ficker JH. [Current status of erlotinib and gefitinib in palliative therapy for NSCLC – does the EGF-R mutation state have any significance?].. Pneumologie 2010; 64: 727-735
  • 63 Wiewrodt R, Serke M, Grohe C. et al. [Employing tyrosine kinase inhibitors in the first line treatment of EGFR-positive metastatic NSCLC – state of the art and recent developments]. Pneumologie 2013; 67: 494-501
  • 64 Douillard JY, Ostoros G, Cobo M. et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer 2014; 110: 55-62
  • 65 Kimura H, Suminoe M, Kasahara K. et al. Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA). Br J Cancer 2007; 97: 778-784
  • 66 He C, Liu M, Zhou C. et al. Detection of epidermal growth factor receptor mutations in plasma by mutant-enriched PCR assay for prediction of the response to gefitinib in patients with non-small-cell lung cancer. Int J Cancer 2009; 125: 2393-2399
  • 67 Reck M, Hagiwara K, Han B. et al. ctDNA Determination of EGFR Mutation Status in European and Japanese Patients with Advanced NSCLC: the ASSESS Study. J Thorac Oncol 2016; 11: 1682-1689
  • 68 Camps C, Jantus-Lewintre E, Cabrera A. et al. The identification of KRAS mutations at codon 12 in plasma DNA is not a prognostic factor in advanced non-small cell lung cancer patients. Lung Cancer 2011; 72: 365-369
  • 69 Douillard JY, Ostoros G, Cobo M. et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 2014; 9: 1345-1353
  • 70 Liu X, Lu Y, Zhu G. et al. The diagnostic accuracy of pleural effusion and plasma samples versus tumour tissue for detection of EGFR mutation in patients with advanced non-small cell lung cancer: comparison of methodologies. J Clin Pathol 2013; 66: 1065-1069
  • 71 Narayan A, Carriero NJ, Gettinger SN. et al. Ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing. Cancer Res 2012; 72: 3492-3498
  • 72 Nygaard AD, Garm Spindler KL, Pallisgaard N. et al. The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer. Lung Cancer 2013; 79: 312-317
  • 73 Takeuchi K, Soda M, Togashi Y. et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18: 378-381
  • 74 Weber B, Meldgaard P, Hager H. et al. Detection of EGFR mutations in plasma and biopsies from non-small cell lung cancer patients by allele-specific PCR assays. BMC Cancer 2014; 14: 294
  • 75 Mok T, Wu YL, Lee JS. et al. Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy. Clin Cancer Res 2015; 21: 3196-3203
  • 76 Sequist LV, Waltman BA, Dias-Santagata D. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3: 75ra26
  • 77 Janne PA, Yang JC, Kim DW. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372: 1689-1699
  • 78 Sequist LV, Soria JC, Goldman JW. et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015; 372: 1700-1709
  • 79 Ohashi K, Maruvka YE, Michor F. et al. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013; 31: 1070-1080
  • 80 Hasegawa T, Sawa T, Futamura Y. et al. Feasibility of Rebiopsy in Non-Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors. Intern Med 2015; 54: 1977-1980
  • 81 Taniguchi K, Uchida J, Nishino K. et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res 2011; 17: 7808-7815
  • 82 Sueoka-Aragane N, Katakami N, Satouchi M. et al. Monitoring EGFRT790M with plasma DNA from lung cancer patients in a prospective observational study. Cancer Science 2016; 107: 162-167
  • 83 Wakelee HA, Gadgeel S, Goldman JW. et al. Epidermal growth factor receptor genotyping of matched urine, plasma and tumor tissue from non-small cell ung cancer patients treated with rociletinib. J Clin Oncol 2016; 34: abstr 9001
  • 84 Oxnard GR, Thress KS, Alden RS. et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2016; 34: 3375-3382
  • 85 Mok T, Wu YL, Ahn MJ. et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M positive lung cancer. N Engl J Med 2016; DOI: 10.1056/NEJMoa1612674.
  • 86 Thress KS, Paweletz CP, Felip E. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 2015; 21: 560-562
  • 87 Solomon BJ, Mok T, Kim DW. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371: 2167-2177
  • 88 Shaw AT, Kim DW, Mehra R. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014; 370: 1189-1197
  • 89 Shaw AT, Kim DW, Nakagawa K. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385-2394
  • 90 Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 2013; 18: 865-875
  • 91 Nilsson RJ, Karachaliou N, Berenguer J. et al. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget 2016; 7: 1066-1075
  • 92 Politi K, Gettinger S. Perfect ALKemy: optimizing the use of ALK-directed therapies in lung cancer. Clin Cancer Res 2014; 20: 5576-5578
  • 93 Goeckenjan G, Sitter H, Thomas M. et al. Prevention, diagnosis, therapy, and follow-up of lung cancer: interdisciplinary guideline of the German Respiratory Society and the German Cancer Society. Pneumologie 2011; 65: 39-59
  • 94 Butts CA, Ding K, Seymour L. et al. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 2010; 28: 29-34
  • 95 Francis G, Stein S. Circulating Cell-Free Tumour DNA in the Management of Cancer. International Journal of Molecular Sciences 2015; 16: 14122-14142
  • 96 Bidard FC, Madic J, Mariani P. et al. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. Int J Cancer 2014; 134: 1207-1213
  • 97 Dawson SJ, Tsui DW, Murtaza M. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013; 368: 1199-1209
  • 98 Forshew T, Murtaza M, Parkinson C. et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 2012; 4: 136ra168
  • 99 Shinozaki M, O'Day SJ, Kitago M. et al. Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer Res 2007; 13: 2068-2074
  • 100 Newman AM, Bratman SV, To J. et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature Medicine 2014; 20: 548-554
  • 101 Bayarri-Lara C, Ortega FG, Cueto Ladron de Guevara A. et al. Circulating Tumor Cells Identify Early Recurrence in Patients with Non-Small Cell Lung Cancer Undergoing Radical Resection. PLoS One 2016; 11: e0148659
  • 102 Allard WJ, Matera J, Miller MC. et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004; 10: 6897-6904
  • 103 Hanssen A, Loges S, Pantel K. et al. Detection of Circulating Tumor Cells in Non-Small Cell Lung Cancer. Front Oncol 2015; 5: 207
  • 104 Hirose T, Murata Y, Oki Y. et al. Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer. Oncol Res 2012; 20: 131-137
  • 105 Hofman V, Ilie MI, Long E. et al. Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non-small-cell lung carcinoma: comparison of the efficacy of the CellSearch Assay and the isolation by size of epithelial tumor cell method. Int J Cancer 2011; 129: 1651-1660
  • 106 Isobe K, Hata Y, Kobayashi K. et al. Clinical significance of circulating tumor cells and free DNA in non-small cell lung cancer. Anticancer Res 2012; 32: 3339-3344
  • 107 Tanaka F, Yoneda K, Kondo N. et al. Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res 2009; 15: 6980-6986
  • 108 Huang CH, Wick JA, Sittampalam GS. et al. A multicenter pilot study examining the role of circulating tumor cells as a blood-based tumor marker in patients with extensive small-cell lung cancer. Front Oncol 2014; 4: 271
  • 109 Yuan D, Chen L, Li M. et al. Isolation and characterization of circulating tumor cells from human gastric cancer patients. J Cancer Res Clin Oncol 2015; 141: 647-660